Homeostasis between epithelial and immune systems and intestinal microbiota is important in controlling the organism's responses to inflammatory stimuli. Cathelicidin is an endogenous peptide that possesses anti- microbial functions. It constitutes a part of the overall innate immune response to protect the host against infection. Recent evidence suggests that cathelicidins (LL-37 in humans and mCRAMP in mice) may modulate responses in inflammation, apoptosis and angiogenesis. However, very little information is available to support a role of cathelicidin in intestinal inflammation. Results from our preliminary studies indicate that cathelicidins and expression of their receptors are increased in the colon of IBD patients and mouse models of colitis, but the particular cells secreting cathelicidin during intestinal inflammation are not known yet. Moreover, short-term administration of mouse cathelicidin (mCRAMP) relieves many aspects of trinitrobenzene sulphonic acid- induced colitis in mice. Therefore, we hypothesize that the inflamed colon releases molecules that stimulate cathelicidin expression from epithelial cells and/or immune cells but these moderately increased cathelicidin levels in the intestine may not be sufficient to counteract severe inflammation. Thus exogenous cathelicidin administration may be necessary to counteract colonic inflammation. In aim 1, we will characterize the cellular cathelicidin expression profile in colons of IBD patients and several mouse models of acute and chronic colitis and we will examine the possibility to administer sodium butyrate to increase endogenous cathelicidin levels to reduce colitis in vivo. Aim 2 will examine the in vivo therapeutic effects of short- and long-term administration of cathelicidin in mouse models of acute and chronic colonic inflammation. Experiments in aim 3 will determine the anti-angiogenic and anti-fibrogenic role of cathelicidin in cultured human intestinal microvascular endothelial cells and fibroblasts. In summary, our proposed experiments will provide important insights into the role of cathelicidins in the pathophysiology of intestinal inflammation and IBD and the mechanisms by which cathelicidins modulate colonic inflammation.